(PQ6) Mesenchymal stem cell based and immunocompetent mouse models of HIV/AIDS KSHV-driven sarcomagenesis

(PQ6) 基于间充质干细胞和免疫活性的 HIV/AIDS 小鼠模型 KSHV 驱动的肉瘤发生

• 批准号: 10228426
• 负责人: Enrique A Mesri
• 金额: $ 57.83万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-08 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10228426
• 关键词: AIDS related cancer; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Affect; Animal Model; Antibodies; Antibody Therapy; Automobile Driving; Biology; Bone Marrow; Cancer Etiology; Cell model; Cells; Collaborations; Development; Doxorubicin; Engraftment; Evaluation; Fibroblast Growth Factor; Genes; Growth; HIV; HIV Infections; HIV-1; Herpesviridae; Herpesviridae Infections; Human; Human Herpesvirus 8; Human immunodeficiency virus test; IGF2 gene; Immune; Immune checkpoint inhibitor; Immunocompetent; Immunologic Deficiency Syndromes; Immunologic Tests; Immunologics; Immunosuppression; Immunotherapeutic agent; Immunotherapy; In Vitro; Inbred BALB C Mice; Incidence; Individual; Infection; Inflammatory; Kaposi Sarcoma; Local Therapy; Mesenchymal Stem Cells; Modeling; Molecular Genetics; Morbidity - disease rate; Mus; Mutation; Nude Mice; Oncogenes; Oncogenic; PD-1/PD-L1; PDGFRA gene; Pathogenesis; Patients; Phenotype; Phosphotransferases; Populations at Risk; Pre-Clinical Model; Preclinical Testing; Principal Investigator; Proteins; Role; Study models; System; T-Lymphocyte; Testing; Therapeutic; Translational Research; Transplantation; Tumorigenicity; Viral; Virus; Virus Diseases; antiretroviral therapy; base; chemotherapy; co-infection; common treatment; cytokine; design; epigenome; exhaustion; global health; immunoregulation; immunosenescence; immunosuppressed; imprint; in vivo; in vivo Model; innovation; lymph nodes; macrophage; mortality; mouse model; mutant; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; pre-clinical; pre-clinical research; programmed cell death ligand 1; programs; stem cell model; targeted treatment; transcriptome; tumor; tumor growth; tumorigenesis; tumorigenic; virology

Kaposi’s sarcoma is an HIV/ AIDS associated malignancy that in spite of the implementation of ART causes significant morbidity and mortality. Pathogenesis based design and testing of new therapeutic approaches are hampered by the paucity of models that reproduce KSHV oncogenesis in the HIV/AIDS setting. There are three major gaps to the experimental ability to model AIDS-KS in vitro and in vivo for translational and preclinical research. 1) A continuous in vitro KSHV-infection to tumorigenesis model that could help dissect microenvironment contributions, and dissect viral and host contributions to viral oncogenesis 2) An in vitro and in vivo model where HIV contributions to KSHV-sarcomagenesis can be identified and studied 3) An immunocompetent model of KSHV-tumorigenesis that could be used to test immune-based therapies. The Mesri and Roy Labs collaboratively developed a comprehensive set of cell and animal models of KSHV-driven Kaposi’s sarcoma that include. I) A mesenchymal-stem cell KSHV- infection to tumorigenesis system--a “de novo” KSHV-induced sarcomagenesis in vitro and in vivo model, which is tightly dependent on the infected-cell microenvironment for tumorigenicity II) A set of mouse models in which KSHV tumorigenesis occurs and can be studied in the context of immunodeficiency, HIV-infection contributions to tumorigenesis and KSHV tumorspecific immunosuppression III) A unique model in which KSHV-infected tumors can be transplanted and grown in HIV infected Balb/c mice. In Aim (1) we will use the MSCs models study the role of KSHV and HIV interactions in viral oncogenesis of HIV/AIDS-KS. In Aim (2) we will determine the mechanisms whereby HIV infection promotes KSHV tumorigenicity in nude and immunocompetent mice. In Aim (3), we will use our model of KSHV-tumorigenesis in HIV infected immunocompetent mice as AIDS-KS preclinical model. We will be able to test immunological therapies to KS such as immunomodulatory molecules, antibody-targeted therapies and checkpoint inhibitor immunotherapies. The propose studies provide unique mouse models to study the role of KSHV HIV co-infection in the pathogenesis of HIV/AIDS-associated Kaposi’s sarcoma and will serve to pre-clinically evaluate novel AIDS-KS therapeutic treatments.

卡波西肉瘤是一种与艾滋病毒/艾滋病相关的恶性肿瘤，尽管实施了 抗逆转录病毒治疗会导致严重的发病率和死亡率。基于病原学的新技术的设计和测试 由于缺乏复制KSHV的模型，治疗方法受到阻碍 艾滋病毒/艾滋病环境中的肿瘤发生。实验能力有三个主要差距 用于翻译和临床前研究的体外和体内模型AIDS-KS。1)连续输入 体外感染KSHV致瘤模型有助于解剖微环境 ，并剖析病毒和宿主对病毒致癌的贡献2)体外和体内 可识别和研究HIV对KSHV-肉瘤形成的贡献的活体模型3) 一种可用于检测免疫基础的KSHV-肿瘤发生的免疫活性模型 治疗。梅斯里和罗伊实验室合作开发了一套全面的细胞和 KSHV驱动的卡波西肉瘤的动物模型包括。1)间充质干细胞KSHV- 对肿瘤发生系统的感染--KSHV诱导的体内外肿瘤 致瘤性与感染细胞微环境密切相关的模型II)A 一组KSHV肿瘤发生的小鼠模型，并可在 免疫缺陷、HIV感染在肿瘤发生和KSHV肿瘤特异性中的作用 免疫抑制III)一种独特的模型，在该模型中感染KSHV的肿瘤可以被移植和 在感染艾滋病毒的Balb/c小鼠中生长。在Aim(1)中，我们将使用MSCs模型来研究KSHV的作用 以及HIV在HIV/AIDS-KS病毒致癌过程中的相互作用。在AIM(2)中，我们将确定 HIV感染促进KSHV在裸鼠和小鼠体内致瘤的机制 免疫能力强的小鼠。在AIM(3)中，我们将使用我们的KSHV-HIV感染的肿瘤发生模型 免疫活性小鼠作为AIDS-KS临床前模型。我们将能够测试免疫学 对KS的治疗，如免疫调节分子、抗体靶向治疗和 检查点抑制免疫疗法。所提出研究提供了独特的小鼠模型 KSHV HIV混合感染在HIV/AIDS相关性卡波西病发病机制中的作用研究 并将用于临床前评估新的AIDS-KS治疗方法。